1. Field of the Invention
The present invention relates to an active agent of the formula I and to a method of treating a disorder associated in part with the overexpression of cytidine deaminase or deoxycytidine deaminase, comprising administering 5-methyl-2',3'-dideoxy-3'-azidocytidine (5mAZC), analog thereof or a pharmaceutically effective salt thereof to a subject in need of such treatment in an amount effective to treat the disorder and ameliorate its symptoms.
2. Description of the Background
The overexpression of cytidine deaminase (CD) is associated with a number of human disorders. For example, certain kinds of leukemias are refractory to the widely used anti-cancer agent cytosine arabinoside (araC). The lack of response to araC has been found to be due primarily either to inactivation of the deoxycytidine kinase gene locus (whose product is required for activation of araC to its cancer-killing form), or to the overexpression of cytidine deaminase or deoxycytidine deaminase (which deactivates araC by deaminating it to an inactive form, araUracil). There is currently no adequate treatment to overcome this resistance to araC due to the cytidine deaminase or deoxycytidine deaminase overexpression.
The overexpression of cytidine deaminase is also implicated in the ineffective cycle of the human immunodeficiency virus (HIV), the virus implicated in AIDS. The initial states of HIV infection are characterized by overexpression of cytidine deaminase by the CD-4+T lymphocytes targeted by the virus. The elimination of this original set of infected cells could be critically important in controlling the level of subsequent infection.
Currently, one treatment for HIV infection and AIDS is the administration of 3'-azido-3'deoxythymidine (AZT). Problems with toxicity, however, have been associated with this treatment. Such toxicity occurs in part due to the fact that AZT is administered systemically, and damages host cells in all replicating tissue compartments.
There is currently a need for a treatment for HIV infection that has the same or improved efficacy of AZT, without the side effects associated with toxicity. One solution to this problem would be a prodrug for AZT which exhibited reduced toxicity to replicating cells, and was preferentially activated to its virus-killing form (AZT) in HIV-infected cells.
In addition, inflammatory cells associated with the symptoms of arthritis have also been shown to overexpress cytidine deaminase.
It would be desirable to provide a relatively non-toxic prodrug that would be preferentially activated to a metabolite that is toxic to the inflammatory cells mediating arthritis.